Endothelins (ET) are paracrine/autocrine factors that act as modulators of vasomotor tone, cell proliferation, hormone production, and nociception through receptor-mediated pathways. The ETA receptor is responsible for the cellular and patho-physiologic effects. Of the two receptors, blockade of ETA may inhibit tumor progression and may modulate pain associated with metastasis. A Phase 1, dose escalation trial of a novel ETA -selective receptor-antagonist, ABT-627, in patients with refractory adenocarcinoma evaluated the safety, pharmacokinetics, tumor response, changes in tumor markers, and changes in pain scores after therapy. ABT-627 was given once a day for 28 days, followed by a 7-day break, with continuation if there was evidence of clinical benefit. Twenty-nine patients (15 prostate, 8 colon, 2 breast, 2 renal, 1 pancreas, 1 lung,) have been enrolled at 7 dose levels (10 - 75mg/day and 37.5 mg/bid). Toxicity has been minimal, with transient Grade 2 headache (35%), rhinitis (91%), mild anorexia (35%) and fatigue (35%) as the most common side effects. No severe hematologic, cardiovascular, hepatic, or renal toxicity has been noted. Pharmacokinetic sampling, on Days 1 and 28, found plasma concentrations increased rapidly and declined biexponentially (half-life of about 22 hours). Dose normalized AUC were linear throughout the range studied. Immunoreactive ET plasma concentrations increased modestly for all dose levels suggesting displacement of the peptide from the receptor. Declines in PSA/CEA after 28 days of treatment were noted in 10/15 (66% - Range 5% - 48%). Declines in pain by > 2 on the visual analog scale and decreases in narcotic use were seen in (2/6) symptomatic men analyzed so far. Measurable responses have not been noted. Eleven patients continued after the initial 28-day period with stable or improved disease-related symptoms. Three patients remained on study up to 8 + months. ABT-627 is well-tolerated. Early tumor marker changes and improvement in pain are encouraging. Phase II trials are underway in prostate cancer.